Project Summary Impairments in cognitive functions that depend on the prefrontal cortex are a common feature of aging, as well as age-related diseases like Alzheimer's disease (AD). These impairments can reduce quality of life and interfere with daily activities including adherence to medication schedules, thereby resulting in additional effects that impact health in the elderly. A potential strategy to augment prefrontal cortex function is to selectively stimulate basal forebrain projections to the prefrontal cortex, increasing acetylcholine release in the dorsolateral prefrontal cortex and stimulating neuronal mechanisms that underlie normal working memory function. We propose to develop such a strategy in rhesus monkeys, and test its ability to improve cognition. This chemogenetic neuromodulation strategy will use a combination of two viruses: one retrogradely-transported vector containing Cre recombinase into dorsolateral prefrontal cortex and a second Cre-dependent DREADD into basal forebrain. This will selectively target basal forebrain neurons projecting to dorsolateral prefrontal cortex. Once this approach has been tested and validated, we will test whether stimulation of neurons of the primate basal forebrain that project to dorsolateral neocortex is effective in offsetting working memory impairment caused by pharmacological antagonism of acetylcholine. This will provide a critical test in a highly translationally-relevant model of the potential for a neurostimulation intervention, targeted at a discrete neuronal circuit, to improve age-related deficits in cognitive functions of the prefrontal cortex.